Substituted tert.-butanol derivatives and antimycotic agents containing these compounds

ABSTRACT

The invention relates to bis-azolyl-substituted t-butanol derivatives defined herein under formula (I) and their use as antimycotic agents. Included in the invention are compositions containing said t-butanol derivatives and methods for using said derivatives and compositions containing them for their antimycotic activity.

The present invention relates to substituted tert.-butanol derivatives,processes for their preparation and antimycotic agents containing thesecompounds.

It has already been disclosed that hydroxypropylimidazoles, such as, forexample,2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-propanol,and 1-hydroxymethyl-azole derivatives, such as, for example,2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol or2-(2-methylphenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)- and-(imidazol-1-yl)-butan-2-ol, and diazolyl-alkanols, such as, forexample, 1,3-di-(imidazol-1-yl)-2-(4-chlorophenyl)-2-propanol, have goodantimycotic properties.

Substituted tert.-butanol derivatives of the formula ##STR1## in whichR¹, R² and R³ are identical or different and represent azolyl,optionally substituted phenoxy, optionally substituted phenylthio,alkylthio, alkenyl, alkinyl, optionally substituted phenylacetylenyl,alkylamino, dialkylamino, optionally substituted phenylamino, optionallysubstituted phenyl-N-alkyl-amino, optionally substituted cycoalkylamino,optionally substituted cycloalkyl-N-alkyl-amino, aminoethoxy,alkylaminoethoxy or dialkylaminoethoxy,

and physiologically acceptable acid addition salts thereof, have nowbeen found, having high antimicrobial, particularly high antimycoticactivity.

It has furthermore been found that the substituted tert.-butanolderivatives of the formula (I) are obtained by a process in which anucleophile of the formula (II)

    R.sup.1 --H                                                (II)

in which

R¹ has the abovementioned meaning,

(a) is reacted with 2,2-dihalogenomethyloxiranes of the formula (III)##STR2## in which Hal represents halogen,

in the presence of a diluent and in the presence of a an acid-bindingagent, or

(b) is reacted with 2-halogenomethyloxiranes of the formula (IV)##STR3## in which R² and Hal have the abovementioned meaning,

in the presence of a diluent and in the presence of an acid-bindingagent, or

(c) is reacted with substituted oxiranes of the formula (V) ##STR4## inwhich R² and R³ have the abovementioned meaning,

in the presence of a diluent and in the presence of an acid-bindingagent.

If desired, an acid can then be added onto the compounds of the formula(I) thus obtained.

The compounds of the formula (I) may have an asymmetric carbon atom, andthey may therefore possibly be obtained in the two optical isomer forms.

Racemate mixtures can be separated into the pure racemates in a knownmanner on the basis of the physicochemical differences of theconstituents, for example by chromatography and/or fractionalcrystallization.

Pure racemates can be resolved according to known methods, for exampleby recrystallization from an optically active solvent, with the aid ofmicro-organisms or by reaction with an optically active acid or basewhich forms salts with the racemic compound and separation of the saltsobtained in this manner, for example on the basis of their differentsolubilities, into the diastereomers from which the antipodes can beliberated by the action of suitable agents. Particularly customaryoptically active acids are, for example, the d- and l-forms of tartaricacid, di-o-toluyltartaric acid, malic acid, mandelic acid,camphorsulphonic acid or quinic acid. Suitable optically active basesare, for example, optically active α-phenylethylamine,α-(1-naphthyl)-ethylamine, quinine, cinchonidine and brucine.Advantageously, the more active of the two antipodes is isolated.

According to the invention it is however also possible to obtain the endproduct in the form of pure racemates or optical antipodes by employingstarting substances, containing one or more asymmetrical C atoms, in theform of the pure racemates or optical antipodes.

The new substituted tert.-butanol derivatives of the formula (I) havepowerful antimycotic properties. Surprisingly, the compounds accordingto the invention exhibit a better in vivo activity, in particular atherapeutically useful in vivo activity, than the compounds2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-imidazol-1-yl)-2-propanol;2-(4-chlorophenoxymethyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol;2-(2-methylphenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)- and-(imidazol-1-yl)-butan-2-ol and1,3-di-(imidazol-1-yl)-2-(4-chlorophenyl)-2-propanol, which are knownfrom the prior art and are closely related compounds structurally andfrom the point of view of their action. The substances according to theinvention thus represent an enrichment of pharmacy.

The new substituted tert.-butanol derivatives are also interestingintermediates. Thus, for example, the compounds of the formula (I) canbe converted into the corresponding ether on the hydroxyl group in thecustomary manner. Furthermore, acyl or carbamoyl derivatives of thecompounds of the general formula (I) can be obtained by reaction with,for example, acyl halides or carbamoyl chlorides in a manner which isknown in principle. The term "acyl" as used herein refers particularlyto carboxylic acid acyl and also sulfonic acid acyl and especially to C₁-C₄ -alkane-carboxylic acid acyl.

Formula (I) provides a general definition of the substitutedtert.-butanol derivatives according to the invention.

Preferred compounds of the formula (I) are those in which

(A)

R¹ and R² are identical or different and represent imidazol-1-yl,1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl or pyrazol-1-yl and

R³ represents phenoxy, phenylthio, phenylamino or phenyl-N-alkyl-aminowith 1 to 4 carbon atoms in the alkyl part, each radical beingoptionally monosubstituted, disubstituted or polysubstituted byidentical or different substituents, possible substituents on phenyl ineach case being: halogen, alkyl with 1 to 6 carbon atoms, alkoxy andalkylthio with in each case 1 to 4 carbon atoms; halogenoalkyl,halogenoalkoxy and halogenoalkylthio with in each case 1 to 4 carbonatoms and 1 to 5 identical or different halogen atoms, such as fluorineand chlorine atoms; cycloalkyl with 5 or 6 carbon atoms; nitro, cyano,hydroxycarbonyl, alkylcarbonyl or alkoxycarbonyl with in each case 1 to4 carbon atoms in the alkyl part, phenyl or phenoxy which is optionallymonosubstituted, disubstituted or polysubstituted by identical ordifferent substituents from the group comprising halogen, nitro,trifluoromethyl and alkyl, with 1 to 2 carbon atoms, the aldehyde groupor the oxime or oxime ether radical;

Other preferred compounds of the formula (I) are those

in which

(B)

R¹ and R² are identical or different and represent imidazol-1-yl;1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl or pyrazol-1-yl and

R³ represents alkylthio with 1 to 12 carbon atoms, alkylamino ordialkylamino with in each case 1 to 4 carbon atoms in each alkyl part,aminoethoxy, alkylaminoethoxy or dialkylaminoethoxy with in each case 1to 4 carbon atoms in each alkyl part, or cycloalkylamino orcycloalkyl-N-alkylamino with in each case 3 to 7 carbon atoms in thecycloalkyl part and 1 to 4 carbon atoms in the alkyl part and in eachcase optionally monosubstituted or polysubstituted in the cycloalkylpart by identical or different substituents, possible substituentsbeing: halogen, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 2carbon atoms.

Further preferred compounds of the formula (I) are those

in which

(C)

R¹ represents imidazol-1-yl; 1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl orpyrazol-1-yl and

R² and R³ are identical or different and have the meanings given abovefor R³ under point (A).

Other preferred compounds of the formula (I) are those

in which

(D)

R¹ represents imidazol-1-yl; 1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl orpyrazol-1-yl and

R² and R³ are identical or different and have the meanings given abovefor R³ under point (B).

Preferred compounds of the formula (I) are likewise those

in which

(E)

R¹, R² and R³ are identical or different and have the meanings givenabove for R³ under points (A) and (B).

Finally, preferred compounds of the formula (I) are also those

in which

(F)

R¹, R² and R³ are identical or different and have the meanings mentionedabove for R¹ under point (A).

Particularly compounds of the formula (I) are those

in which

(A)

R¹ and R² are identical or different and represent imidazol-1-yl;1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl or pyrazol-1-yl, and

R³ represent phenoxy, phenylthio, phenylamino or phenyl-N-alkyl-aminowith 1 or 2 carbon atoms in the alkyl part, each radical optionallybeing monosubstituted or di- or tri-substituted by identical ordifferent substituents, possible substituents on the phenyl in each casebeing: fluorine, chlorine, bromine, methyl, ethyl, isopropyl,tert.-butyl, 2-methyl-but-2-yl, methoxy, ethoxy, methylthio,trifluoromethylthio, cyclohexyl, nitro, cyano, hydroxycarbonyl,methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, or phenyl or phenoxy,in each case optionally monosubstituted or di- or tri-substituted byidentical or different substituents from the groups comprising chlorine,nitro, trifluoromethyl and methyl, or the aldehyde group,hydroxyiminoethyl or methoxyiminomethyl.

Other particularly preferred compounds of the formula (I) are those

in which

(B)

R¹ and R² are identical or different and represent imidazol-1-yl;1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl or pyrazol-1-yl and

R³ represents methylthio, ethylthio, buthylthio or dodecylthio, oralkylamino or dialkylamino with in each case 1 or 2 carbon atoms in eachalkyl part, or aminoethoxy, alkylaminoethoxy or dialkylaminoethoxy within each case 1 or 2 carbon atoms in each alkyl part, orcyclopropylamino, cyclopentylamino, cyclohexylamino,cyclopropyl-N-methyl-amino, cyclopentyl-N-methyl-amino orcyclohexyl-N-methyl-amino, in each case optionally mono-, di- ortri-substituted in the cycloalkyl part by identical or differentsubstituents, possible substituents being: chlorine, bromine, methyl,ethyl, isopropyl and methoxy.

Particularly preferred compounds of the formula (I) are furthermorethose

in which

(C')

R¹ represents imidazol-1-yl; 1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl orpyrazol-1-yl and

R² and R³ are identical or different and have the meanings mentionedabove for R³ under point (A').

Further particularly preferred compounds of the formula (I) are those

in which

(D')

R¹ represents imidazol-1-yl; 1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl orpyrazol-1-yl and

R² and R³ are identical or different and have the meanings given abovefor R³ under point (B')

Particularly preferred compounds of the formula (I) are likewise those

in which

(E')

R¹, R² and R³ are identical or different and have the meanings givenabove for R³ under points (A') and (B').

Finally, particularly preferred compounds of the formula (I) are alsothose

in which

(F')

R¹, R² and R³ are identical or different and have the meanings givenabove for R¹ under point (A').

The following compounds of the formula (I) may be mentionedspecifically, in addition to the compounds mentioned in the preparationexamples:

    ______________________________________                                         ##STR5##                      (I)                                            R.sup.1  R.sup.2       R.sup.3                                                ______________________________________                                         ##STR6##                                                                               ##STR7##                                                                                    ##STR8##                                               ##STR9##                                                                               ##STR10##                                                                                   ##STR11##                                              ##STR12##                                                                              ##STR13##                                                                                   ##STR14##                                              ##STR15##                                                                              ##STR16##                                                                                   ##STR17##                                              ##STR18##                                                                              ##STR19##                                                                                   ##STR20##                                              ##STR21##                                                                              ##STR22##                                                                                   ##STR23##                                              ##STR24##                                                                              ##STR25##                                                                                   ##STR26##                                              ##STR27##                                                                              ##STR28##                                                                                   ##STR29##                                              ##STR30##                                                                              ##STR31##                                                                                   ##STR32##                                              ##STR33##                                                                              ##STR34##    (C.sub.2 H.sub.5).sub.2 NCH.sub.2 CH.sub.2O             ##STR35##                                                                              ##STR36##                                                                                   ##STR37##                                              ##STR38##                                                                              ##STR39##                                                                                   ##STR40##                                              ##STR41##                                                                              ##STR42##                                                                                   ##STR43##                                              ##STR44##                                                                              ##STR45##                                                                                   ##STR46##                                              ##STR47##                                                                              ##STR48##                                                                                   ##STR49##                                             ______________________________________                                    

If, for example, 2,2-di(chloromethyl)-oxirane and 1,2,4-triazole areused as the starting substances, the course of the reaction in process(a) according to the invention can be represented by the followingequation: ##STR50##

If, for example, 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane and1,2,4-triazole are used as the starting substances, the course of thereaction in process (b) according to the invention can be represented bythe following equation: ##STR51##

If, for example, 2,2-di(2,4-dichlorophenoxymethyl)-oxirane and1,2,4-triazole are used as the starting substances, the course of thereaction in process (c) according to the invention can be represented bythe following equation: ##STR52##

Formula (II) provides a general definition of the nucleophiles to beused as starting substances for processes (a), (b) and (c) according tothe invention. In this formula, R¹ preferably represents those radicalswhich have already been mentioned as preferred for this substituent inconnection with the description of the substances of the formula (I)according to the invention.

The nucleophiles of the formula (II) are generally known compounds oforganic chemistry.

Formula (III) provides a general definition of the2,2-dihalogenomethyloxiranes also to be used as starting substances forprocess (a) according to the invention. In this formula, Hal preferablyrepresents chlorine or bromine.

The 2,2-dihalogenomethyloxiranes of the formula (III) are known (compareBeilstein, E III (1), pages 1587-1588), or they can be obtained in aknown manner, in which 3-halogeno-2-halogenomethylpropenes of theformula (VI) ##STR53## in which Hal has the abovementioned meaning,

are either first reacted with a tert.-butoxyhalide to give1,3-dihalogeno-2-halogenomethyl-2-propanols of the formula (VII)##STR54## in which Hal has the abovementioned meaning,

and these are then epoxidised in the presence of calcium hydroxide togive the desired 2,2-dihalogenomethyloxiranes of the formula (III) (inthis context, compare also Beilstein, E III (1), pages 1587-1588); orepoxidised directly in the presence of peracids, such as, for example,peracetic acid, perpropionic acid or m-chloroperbenzoic acid, to givethe desired 2,2-dihalogenomethyloxiranes of the formula (III).

Formula (IV) provides a general definition of the2-halogenomethyloxiranes also to be used as starting substances forprocess (b) according to the invention. In this formula, R² preferablyrepresents those radicals which have already been mentioned as preferredfor this substituent in connection with the description of thesubstances of the formula (I) according to the invention. Hal preferablyrepresents chlorine or bromine.

The 2-halogenomethyloxiranes of the formula (IV) are not yet known.However, they can be obtained in a generally customary manner, in whicheither 2,2-dihalogenomethyloxiranes of the formula (III) are reactedwith a nucleophile of the formula (II); or3-halogeno-2-halogenomethyl-propenes of the formula (VI) are firstreacted with a nucleophile of the formula (II), if appropriate in theform of an alkali metal salt, to give propenes of the formula (VIII)##STR55## in which Hal and R¹ have the abovementioned meaning,

and these are then epoxidised in the presence of peracids to give thedesired 2-halogenomethyloxiranes of the formula (IV).

Formula (V) provides a general definition of the oxiranes also to beused as starting substances for process (c) according to the invention.In this formula, R² and R³ preferably represent those radicals whichhave already been mentioned as preferred for the substituent inconnection with the description of the substances of the formula (I)according to the invention.

The substituted oxiranes of the formula (V) are not yet known. However,they can be obtained in a generally customary manner, in which either2,2-dihalogenomethyloxiranes of the formula (III) are reacted with anucleophile of the formula (II); or 3-halogeno-2-halogenomethyl-propenesof the formula (VI) are reacted with a nucleophile of the formula (II),if appropriate in the form of an alkali metal salt, to give propenes ofthe formula (IX) ##STR56## in which R¹ has the abovementioned meaning,

and these are then epoxidised in the presence of peracids to give thedesired oxiranes of the formula (V); or ketones of the formula (X)##STR57## in which R¹ and R² have the abovementioned meaning,

are epoxidised with dimethylsulphonium methylide in a manner which isknown per se.

Preferred possible diluents for processes (a), (b) and (c) according tothe invention are inert organic solvents. These include, preferably,ketones, such as, in particular, acetone and methyl ethyl ketone;nitriles, such as, in particular, acetonitrile; alcohols, such as, inparticular, ethanol and isopropanol; ethers, such as, in particular,tetrahydrofuran or dioxane; formamides, such as, in particular,dimethylformamide; aromatic and halogenated hydrocarbons, such astoluene and chlorobenzene.

If necessary, processes (a), (b) and (c) according to the invention arecarried out in the presence of acid-binding agents. All the inorganic ororganic acid-binding agents which can usually be used may be added, suchas alkali metal hydroxides and alkali metal carbonates, for examplesodium hydroxide and potassium hydroxide and sodium carbonate andpotassium carbonate; or ammonia or such as lower tertiary alkylamine,preferably having 1 to 4 carbon atoms in each alkyl group, C₄ -C₇-cycloalkylamines or aralkylamines, for example triethylamine,N,N-dimethyl-C₄ -C₇ -cyclohexylamine, dicyclohexylamine orN,N-dimethylbenzylamine, and furthermore pyridine anddiazobicyclooctane, as well as an appropriate excess of imidazole ortriazole.

The reaction temperatures can be varied within a substantial range incarrying out processes (a), (b) and (c) according to the invention. Ingeneral, the reaction is carried out between about 20° and about 150°C., preferably at 20° to 120° C.

In carrying out processes (a), (b) and (c) according to the invention,in each case the stoichiometrically required amount up to a 3-molarexcess required amount of nucleophile of the formula (II) and thestoichiometric amounts up to a 2-molar excess of acid-binding agent areused per mol of oxiranes of the formulae (III), (IV) and (V). Thecompounds of the formula (I) are isolated in the customary manner.

All the physiologically acceptable acids can be used for the preparationof acid addition salts of the compounds of the formula (I). Theseinclude, preferably, the hydrogen halide acids, such as, for example,hydrochloric acid and hydrobromic acid, in particular hydrochloric acid,and furthermore phosphoric acid, nitric acid, sulphuric acid,monofunctional and bifunctional carboxylic acids and hydroxycarboxylicacids, such as, for example, acetic acid, maleic acid, succinic acid,fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acidand lactic acid, and sulphonic acids, such as, for example,p-toluenesulphonic acid and 1,5-naphthalenedisulphonic acid.

The salts of compounds of the formula (I) can be obtained in a simplemanner by customary salt formation methods, for example by dissolving acompound of the formula (I) in a suitable inert solvent and adding theacid, for example hydrochloric acid, and they can be isolated in a knownmanner, for example by filtration, and if necessary purified by washingwith an inert organic solvent.

Certain compounds of the formula (I) can also be obtained by a processin which di(halogenomethyl)-carbinols of the formula (XI) ##STR58## inwhich Hal has the abovementioned meaning and

R⁴ represents optionally substituted phenylthio, alkylthio, alkylamino,dialkylamino, optionally substituted phenylamino, optionally substitutedphenyl-N-alkyl-amino, optionally substituted cycloalkylamino oroptionally substituted cycloalkyl-N-alkylamino,

under the conditions of process (a). In the carbinols of formula (XI),in defining R⁴, --unless otherwise specified--each alkyl moietypreferably contains 1 to 6 (especially 1 to 4) carbon atoms andcycloalkyl preferably contains 4 to 7 (especially 5 or 6) ring members.Optional substituents on the phenyl or cycloalkyl moieties include C₁-C₄ -alkyl or alkoxy or halogen (especially bromine, chlorine orfluorine.

The compounds of the formula (I) according to the invention and theirphysiologically acceptable acid addition salts display antimicrobialactions, in particular powerful antimycotic action in warm-bloodedanims. They possess a very broad antimycotic action spectrum, especiallyagainst dermatophytes and blastomyces as well as biphase fungi, forexample against species of Candida, such as Candida albicans, species ofEpidermophyton, such as Epidermophyton floccosum, species ofAspergillus, such as Aspergillus niger and Aspergillus fumigatus,species of Trichophyton, such as Trichophyton mentagrophytes, species ofMicrosporon, such as Microsporon felineum and species of Torulopsis,such as Torulopsis glabrata. The listing of these micro-organisms in noway implies a limitation of the germs which can be combated but is onlyof illustrative character.

The present invention includes pharmaceutical formulations which, inaddition to non-toxic, inert pharmaceutically suitable excipients,contain one or more active compounds according to the invention, orwhich consist of one or more active compounds according to theinvention, as well as processes for the preparation of theseformulations.

The present invention also includes pharmaceutical formulations indosage units. This means that the formulations are in the form ofindividual parts, for example tablets, dragees, capsules, pills,suppositories and ampoules, of which the content of active compoundcorresponds to a fraction of a multiple of an individual dose. Thedosage units can contain, for example, 1, 2, 3 or 4 individual doses or1/2, 1/3 or 1/4 of an individual dose. An individual dose preferablycontains the amount of active compound which is given in oneadministration and which usually corresponds to a whole, a half, a thirdor a quarter of a daily dose.

By non-toxic, inert pharmaceutically suitable excipients there are to beunderstood solid, semi-solid or liquid diluents, fillers andformulations auxiliaries of every kind.

Tablets, dragees, capsules, pills, granules, suppositories, solutions,suspensions and emulsions, pastes, ointments, gels, creams, lotions,powders and sprays may be mentioned as preferred pharmaceuticalformulations.

Tablets, dragees, capsules, pills and granules can contain the activecompound or compounds alongside the customary excipients, such as (a)fillers and extenders, for example starches, lactose, sucrose, glucose,mannitol and silica, (b) binders, for example carboxymethylcellulose,alginates, gelatin and polyvinylpyrrolidone, (c) humectants, for exampleglycerol, (d) disintegrating agents, for example agar-agar, calciumcarbonate and sodium bicarbonate, (e) solution retarders, for exampleparaffin, and (f) resorption accelerators, for example quaternaryammonium compounds, (g) wetting agents, for example cetyl alcohol andglycerol monostearate, (h) adsorbents, for example kaolin and bentonite,and (i) lubricants, for example talc, calcium stearate and magnesiumstearate and solid polyethylene glycols, or mixtures of the compoundslisted under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided withthe customary coatings and shells, optionally containing opacifyingagents, and can also be of such composition that they release the activecompound or compounds only, or preferentially, in a certain part of theintestinal tract, optionally in a delayed manner, examples of embeddingcompositions which can be used being polymeric substances and waxes.

The active compound or compounds, optionally together with one or moreof the abovementioned excipients can also be a micro-encapsulated form.

Suppositories can contain, in addition to the active compound orcompounds, the customary water-soluble or water-insoluble excipients,for example polyethylene glycols, fats, for example cacao fat, andhigher esters (for example C₁₄ -alcohol with C₁₆ -fatty acid), ormixtures of these substances.

Ointments, pastes, creams and gels can contain, in addition to theactive compound or compounds, the customary excipients, for exampleanimal and vegetable fats, waxes, paraffins, starches, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silica, talc and zinc oxide, or mixtures of these substances.

Powders and sprays can contain, in addition to the active compound orcompounds, the customary excipients, for example lactose, talc, silica,aluminium hydroxide, calcium silicate and polyamide powders or mixturesof these substances. Sprays can additionally contain the customarypropellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compoundor compounds, the customary excipients, such as solvents, solubilisingagents and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, especially cottonseed oil, groundnut oil, maize germ oil, oliveoil, castor oil and sesame oil, glycerol, glycerol-formal,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitane, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain, in addition to the active compound orcompounds, the customary excipients, such as liquid diluents, forexample water, ethyl alcohol or propylene glycol, suspending agents, forexample ethoxylated isostearyl alcohols, polyoxyethylene sorbitol estersand sorbitane esters, micro-crystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances.

The formulation forms mentioned can also contain colorants,preservatives and additives which improve the odour and flavour, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical formulations in a concentration of about0.1 to 99.5, preferably of about 0.5 to 95, % by weight of the totalmixture.

The abovementioned pharmaceutical formulations can also contain otherpharmaceutical active compounds in addition to the active compoundsaccording to the invention.

The abovementioned pharmaceutical formulations are prepared in thecustomary manner according to known methods, for example by mixing theactive compound or compounds with the excipient or excipients.

The present invention also includes the use of the active compoundsaccording to the invention, and of pharmaceutical formulations whichcontain one or more active compounds according to the invention, for thetreatment of the above mentioned diseases.

The active compounds or the pharmaceutical formulations can beadministered locally, orally, parenterally, intraperitoneally and/orrectally, preferably parenterally, and in particular intravenously.

In general, it has proved advantageous in medicine, to administer theactive compound or compounds according to the invention in total amountsof about 10 to about 300, preferably 50 to 200, mg/kg of body weightevery 24 hours, optionally in the form of several individualadministrations, in order to achieve the desired results.

However, it can be necessary to deviate from the dosages mentioned, andin particular to do so as a function of the species and the body weightof the subject to be treated, the nature and severity of the disease,the nature of the formulation and of the administration of themedicament and the time or interval over which the administration takesplace. Thus it can in some cases suffice to manage with less than theabovementioned amount of active compound, whilst in other cases theabovementioned amount of active compound must be exceeded. Theparticular optimum dosage required and the type of administration of theactive compounds can easily be determined by anyone skilled in the arton the basis of his expert knowledge.

Preparation Examples EXAMPLE 1 AND 2 ##STR59##

(process b)

9.4 g (0.04 mol) of 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane areadded dropwise to a mixture of 13.6 g (0.2 mol) of 1,2,4-triazole and13.8 g (0.1 mol) of potassium carbonate in 200 ml of acetone, whilststirring. The mixture is stirred at room temperature for 15 hours andthen under reflux for 22 hours. Thereafter, the reaction mixture isfiltered cold and the filtrate is concentrated in vacuo. The oilyresidue is dissolved in chloroform and the solution is washed withwater, dried over sodium sulphate and purified chromatographically(silica gel 60 Merck, chloroform/methanol=20/1). 5.8 g (43% of theory)of2-(4-chlorophenoxymethyl)-1,3-di-(1,2,4-triazol-1-yl)-2-hydroxypropaneof melting point 99° C. (Example 1) and 2.0 g (15% of theory) of2-(4-chlorophenoxymethyl)-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-4-yl)-propane(Example 2) of melting point 160° C. are obtained.

PREPARATION OF THE STARTING SUBSTANCE ##STR60##

(1st variant)

12.85 g (0.1 mol) of 4-chlorophenol in 50 ml of acetone are addeddropwise to a mixture of 14.1 g (0.1 mol) of2,2-di(chloromethyl)-oxirane and 13.8 g (0.1 mol) of potassium carbonatein 200 ml of acetone. The mixture is heated under reflux for 18 hours,left to cool and filtered. The filtrate is concentrated in vacuo, theresidue is dissolved in chloroform and the solution is washed withwater, dried over sodium sulphate and concentrated. Purification of theresidue by distillation gives 7.6 g (32.5% of theory) of2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane of boiling point 150°C./0.5 mbar.

(2nd variant)

0.5 mol of sodium 4-chlorophenolate in acetonitrile are added dropwiseto a solution of 125 g (1 mol) of 3-chloro-2-chloromethylpropene in 50ml of acetonitrile. After addition of 0.5 g of sodium iodide, thereaction mixture is heated under reflux for 12 hours and is thenfiltered cold. The filtrate is concentrated in vacuo. The residue isdissolved in methylene chloride and the solution is washed with water,dried over sodium sulphate and concentrated. 58.6 g of about 60% pure2-chloromethyl-3-(4-chlorophenoxy)-propene are obtained and aredissolved in 500 ml of methylene chloride, and 43 g (0.25 mol) of3-chloroperbenzoic acid are added.

The mixture is stirred at room temperature for 24 hours and filtered.The filtrate is washed with aqueous 10% strength sodium thiosulphatesolution, dried over sodium sulphate and concentrated in vacuo.Purification of the residue by distillation gives 30 g (12.9% of theory)of 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane of refractive indexn_(D) ²⁰ 1.5465.

EXAMPLE 3, 4 AND 5 ##STR61##

(Processes b and c)

23.5 g of a mixture of2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane and2,2-bis(2,4-dichlorophenoxymethyl)-oxirane are added dropwise to asolution of 20.7 g (0.3 mol) of 1,2,4-triazole and 13.8 g (0.1 mol) ofpotassium carbonate in 200 ml of acetone. The reaction mixture isstirred under reflux for 20 hours. Thereafter, the mixture is filteredcold and the filtrate is concentrated in vacuo. The residue is dissolvedin chloroform and the solution is washed with water, dried over sodiumsulphate and purified and separated by chromatography (silica gel 60Merck). The column is first eluted with chloroform. The eluate therebyobtained is concentrated by distilling off the solvent, and the residueis stirred with diethyl ether. 4.8 g of1,3-bis-(2,4-dichlorophenoxy)-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-propane(Example 5) of melting point 136° C. are obtained.

The column is then eluted with chloroform/methanol: 40/1. The eluatethereby obtained is concentrated by distilling off the solvent, and theresidue is stirred with acetonitrile. 3.9 g of2-(2,4-dichlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxy-propane(Example 3) of melting point 138° C. are obtained.

Finally, the column is eluted with chloroform/methanol: 20/1. The eluatethereby obtained is concentrated by distilling off the solvent, and theresidue is stirred with acetonitrile. 3.7 g of2-(2,4-dichlorophenoxymethyl)-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-4-yl)-propane(Example 4) of melting point 182° C. are obtained.

PREPARATION OF THE STARTING SUBSTANCES ##STR62##

A mixture of 14.1 g (0.1 mol) of 2,2-di(chloromethyl)-oxirane, 13.8 g(0.1 mol) of potassium carbonate and 16.3 g (0.1 mol) of2,4-dichlorophenol in 150 ml of acetone is heated to 60° C. for 15 hoursand is then filtered cold, and the filtrate is concentrated in vacuo.The residue is taken up in methylene chloride and the solution is washedwith water, dried over sodium sulphate and concentrated. 23.5 g of anoily mixture which, on the basis of determination by gas chromatography,contains 47% of 2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane(Example IV-2) and 24.9% of 2,2-bis(2,4-dichlorophenoxymethyl)-oxirane(Example V-1), in addition to 14.9% of unreacted2,2-di(chloromethyl)-oxirane, are obtained.

If necessary, this mixture can be separated by chromatography,2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane (Example IV-2) ofrefractive index n_(D) ²⁰ 1.5568 and2,2-bis-(2,4-dichlorophenoxymethyl)-oxirane (Example V-1) of meltingpoint 64° C. being obtained.

EXAMPLE 6 ##STR63##

(Process b)

7.1 g (55% of theory) of2-(2-chlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxy-propaneof melting point 95° C. are obtained according to Example 1/2 from 8.9 g(0.038 mol) of 2-chloromethyl-2-(2-chlorophenoxymethyl)-oxirane, 5 g(0.038 mol) of potassium carbonate and 6.9 g (0.1 mol) of 1,2,4-triazolein 200 ml of acetone, after purification of the reaction product bychromatography (silica gel 60, Merck, chloroform/methanol=40/1).

PREPARATION OF THE STARTING SUBSTANCE ##STR64##

9.1 g (39% of theory) of2-chloromethyl-2-(2-chlorophenoxymethyl)-oxirane of refractive indexn_(D) ²⁰ 1.5463 are obtained according to Example 1/2 (preparation ofthe starting substance, 1st variant), from 12.85 g (0.1 mol) of2-chlorophenol in 50 ml of acetone and 14.1 g (0.1 mol) of2,2-di(chloromethyl)-oxirane as well as 13.8 g (0.1 mol) of potassiumcarbonate in 200 ml of acetone.

EXAMPLE 7 ##STR65##

(Process a)

28.2 g (0.2 mol) of 2,2-di(chloromethyl)-oxirane are added dropwise to amixture of 82.5 g (1.2 mol) of 1,2,4-triazole and 82.5 g (0.6 mol) ofpotassium carbonate in 400 ml of acetone, whilst stirring. The reactionmixture is stirred under reflux for 50 hours and filtered and thefiltrate is concentrated in vacuo. The oily residue is chromatographed(silica gel 60, Merck, chloroform/methanol=20/1). 5.9 g (10.7% oftheory) of1,3-di-(1,2,4-triazol-1-yl)-2-hydroxy-2-(1,2,4-triazol-4-yl-methyl)-propaneof melting point 220° C. are obtained.

EXAMPLE 8 AND 9 ##STR66##

(Process b)

12.1 g (57.5% of theory) of2-(4-chlorophenylthiomethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxy-propane(Example 8) of melting point 150° C. and 4.6 g (22% of theory) of2-(4-chlorophenylthiomethyl)-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-4-yl)-propane(Example 9) of melting point 186° C. are obtained according to Example1/2, from 14.8 g (0.06 mol) of2-chloromethyl-2-(4-chlorophenylthiomethyl)-oxirane, 8.3 g (0.12 mol) of1,2,4-triazole and 8.3 g (0.06 mol) of potassium carbonate in 200 ml ofacetone.

PREPARATION OF THE STARTING PRODUCT ##STR67##

5.4 g (0.1 mol) of sodium methylate are introduced in portions into amixture of 16.9 g (0.12 mol) of 2,2-di(chloromethyl)-oxirane and 14.5 g(0.1 mol) of 4-chlorothiophenol in 200 ml of acetonitrile. The reactionmixture is subsequently stirred for 4 hours and filtered and thefiltrate is concentrated in vacuo. The residue is dissolved in methylenechloride and the solution is washed with water, dried over sodiumsulphate and concentrated. The oil which remains is distilled. 18.2 g(73% of theory) of 2-chloromethyl-2-(4-chlorophenylthiomethyl)-oxiraneof refractive index n_(D) ²⁰ 1.5895 are obtained.

The following end products of the formula (I) ##STR68## in Table 1 areobtained in a corresponding manner and by the processes according to theinvention using analogous reactants and reaction conditions:

                                      TABLE 1                                     __________________________________________________________________________    Example                                                 Melting point         No.  R.sup.1     R.sup.2             R.sup.3            (°C.) or                                                               n.sub.D.sup.20        __________________________________________________________________________    10                                                                                  ##STR69##                                                                                 ##STR70##                                                                                         ##STR71##         166                   11   "           "                                                                                                  ##STR72##          90                   12   "           "                                                                                                  ##STR73##         140                   13   "           "                                                                                                  ##STR74##         179                   14   "           "                                                                                                  ##STR75##         130                   15   "                                                                                          ##STR76##                                                                                         ##STR77##         146                   16   "           "                                                                                                  ##STR78##         150                   17   "           "                                                                                                  ##STR79##         204                   18   "           "                                                                                                  ##STR80##         166                   19                                                                                  ##STR81##                                                                                 ##STR82##                                                                                         ##STR83##         120                   20                                                                                  ##STR84##                                                                                 ##STR85##                                                                                         ##STR86##         130                   21                                                                                  ##STR87##                                                                                 ##STR88##                                                                                         ##STR89##          77                   22                                                                                  ##STR90##                                                                                 ##STR91##                                                                                         ##STR92##          95                   23                                                                                  ##STR93##                                                                                 ##STR94##                                                                                         ##STR95##          92                   24                                                                                  ##STR96##                                                                                 ##STR97##                                                                                         ##STR98##         130                   25                                                                                  ##STR99##                                                                                 ##STR100##                                                                                        ##STR101##        100                   26                                                                                  ##STR102##                                                                                ##STR103##                                                                                        ##STR104##        108                   27                                                                                  ##STR105##                                                                                ##STR106##                                                                                        ##STR107##         72                   28                                                                                  ##STR108##                                                                                ##STR109##                                                                                        ##STR110##         84                   29                                                                                  ##STR111##                                                                                ##STR112##                                                                                        ##STR113##        158                   30   "                                                                                          ##STR114##                                                                                        ##STR115##        112                   31   "                                                                                          ##STR116##                                                                                        ##STR117##        118                   32   "                                                                                          ##STR118##                                                                                        ##STR119##        162                   33   "           "                                                                                                  ##STR120##        188                   34   "                                                                                          ##STR121##                                                                                        ##STR122##        110                   35   "           "                                                                                                  ##STR123##         70                   36   "                                                                                          ##STR124##                                                                                        ##STR125##        138                   37   "                                                                                          ##STR126##                                                                                        ##STR127##        162                   38   "                                                                                          ##STR128##                                                                                        ##STR129##        174                   39   "                                                                                          ##STR130##                                                                                        ##STR131##        134                   40   "                                                                                          ##STR132##                                                                                        ##STR133##         84                   41   "                                                                                          ##STR134##                                                                                        ##STR135##        120                   42   "           "                                                                                                  ##STR136##         74                   43   "                                                                                          ##STR137##                                                                                        ##STR138##         95                   44   "                                                                                          ##STR139##                                                                                        ##STR140##         75                   45   "                                                                                          ##STR141##                                                                                        ##STR142##         93                   46   "                                                                                          ##STR143##         SC.sub.2 H.sub.5    46                   47   "           "                                                                                                  ##STR144##         75                   48   "           "                                                                                                  ##STR145##         70                   49   "                                                                                          ##STR146##                                                                                        ##STR147##         90                   50   "                                                                                          ##STR148##                                                                                        ##STR149##        116                   51   "                                                                                          ##STR150##                                                                                        ##STR151##        128                   52   "                                                                                          ##STR152##                                                                                        ##STR153##        142                   53   "                                                                                          ##STR154##         "                  186                   54   "                                                                                          ##STR155##                                                                                        ##STR156##        149                   55   "                                                                                          ##STR157##         "                  155                   56   "                                                                                          ##STR158##                                                                                        ##STR159##        1.5820                57   "                                                                                          ##STR160##         "                   45                   58   "                                                                                          ##STR161##                                                                                        ##STR162##        130                   59   "                                                                                          ##STR163##                                                                                        ##STR164##        150                   60   "                                                                                          ##STR165##                                                                                        ##STR166##        126                   61   "                                                                                          ##STR167##                                                                                        ##STR168##         95                   62   "                                                                                          ##STR169##                                                                                        ##STR170##        170                   63   "                                                                                          ##STR171##                                                                                        ##STR172##        142                   64   "                                                                                          ##STR173##                                                                                        ##STR174##        177                   65   "                                                                                          ##STR175##                                                                                        ##STR176##         90                   66   "                                                                                          ##STR177##                                                                                        ##STR178##         70                   67   "                                                                                          ##STR179##                                                                                        ##STR180##        1.5620                68   "           "                                                                                                  ##STR181##        1.5698                69   "           "                                                                                                  ##STR182##        1.5600                70   "           "                                                                                                  ##STR183##         80                   71   "                                                                                          ##STR184##                                                                                        ##STR185##        108                   72   "                                                                                          ##STR186##                                                                                        ##STR187##        1.5608                73   "           "                                                                                                  ##STR188##        126                   74   "                                                                                          ##STR189##                                                                                        ##STR190##        142                   75   "           "                                                                                                  ##STR191##        144                   76   "           "                                                                                                  ##STR192##        viscous oil           77   "                                                                                          ##STR193##                                                                                        ##STR194##        168                   78   "                                                                                          ##STR195##                                                                                        ##STR196##        146                   79   "                                                                                          ##STR197##                                                                                        ##STR198##        108                   80   "                                                                                          ##STR199##                                                                                        ##STR200##        150                   81   "                                                                                          ##STR201##                                                                                        ##STR202##        188                   82   "                                                                                          ##STR203##                                                                                        ##STR204##         98                   83   "                                                                                          ##STR205##                                                                                        ##STR206##        164                   84   "                                                                                          ##STR207##                                                                                        ##STR208##        166                   85   "                                                                                          ##STR209##                                                                                        ##STR210##        194                   86   "                                                                                          ##STR211##                                                                                        ##STR212##        128                   87   "                                                                                          ##STR213##                                                                                        ##STR214##        141                   88   "                                                                                          ##STR215##                                                                                        ##STR216##        115                   89   "           "                                                                                                  ##STR217##         96                   90   "                                                                                          ##STR218##                                                                                        ##STR219##        159                   91   "                                                                                          ##STR220##                                                                                        ##STR221##        160                   92   "                                                                                          ##STR222##                                                                                        ##STR223##        184                   93   "                                                                                          ##STR224##                                                                                        ##STR225##        186                   94   "                                                                                          ##STR226##                                                                                        ##STR227##        1.5750                95   "                                                                                          ##STR228##                                                                                        ##STR229##        142                   96   "                                                                                          ##STR230##                                                                                        ##STR231##        190                   97   "                                                                                          ##STR232##                                                                                        ##STR233##        120                   98   "                                                                                          ##STR234##                                                                                        ##STR235##        130                   99   "                                                                                          ##STR236##                                                                                        ##STR237##        154                   100  "                                                                                          ##STR238##                                                                                        ##STR239##         80                   101  "                                                                                          ##STR240##                                                                                        ##STR241##        114                   102  "                                                                                          ##STR242##                                                                                        ##STR243##        169                   103  "           "                                                                                                  ##STR244##        140                   104  "           "                                                                                                  ##STR245##        154                   105  "                                                                                          ##STR246##                                                                                        ##STR247##         50                   106  "                                                                                          ##STR248##                                                                                        ##STR249##         75                   107  "                                                                                          ##STR250##         S(CH.sub.2).sub.11CH.sub.3                                                                        70                   108                                                                                 ##STR251##                                                                                ##STR252##                                                                                        ##STR253##        169                   109  "           S(CH.sub.2).sub.11 CH.sub.3                                                                       S(CH.sub.2).sub.11 CH.sub.3                                                                       84                   110  "                                                                                          ##STR254##         S(CH.sub.2).sub.11 CH.sub.3                                                                       82                   111                                                                                 ##STR255## S(CH.sub.2).sub.11 CH.sub.3                                                                       S(CH.sub.2).sub.11 CH.sub.3                                                                       51                   112  "                                                                                          ##STR256##                                                                                        ##STR257##         96                   113  "                                                                                          ##STR258##                                                                                        ##STR259##         92                   114  "                                                                                          ##STR260##                                                                                        ##STR261##        130                   115  "                                                                                          ##STR262##         SC(CH.sub.3).sub. 3                                                                               70                   116  "                                                                                          ##STR263##         SC(CH.sub.3).sub.3  91                   __________________________________________________________________________

The following intermediates of the formula (IV) ##STR264## in Table 2are obtained according to the preparation examples recited above byusing analogous reactants and reaction conditions, and the generalstatements relating to the processes

                  TABLE 2                                                         ______________________________________                                                                          Boiling point                               Example                           (°C.)/mbar                           No.    R.sup.2             Hal    or n.sub.D.sup.20                           ______________________________________                                        (IV-5)                                                                                ##STR265##         Cl     100/0.2                                     (IV-6)                                                                                ##STR266##         Cl     145/0.1                                     (IV-7)                                                                                ##STR267##         Cl     155/0.3                                     (IV-8)                                                                                ##STR268##         Cl     1.5842                                      (IV-9)                                                                                ##STR269##         Cl     190/0.2                                     (IV-10)                                                                               ##STR270##         Cl     100/0.1                                     (IV-11)                                                                               ##STR271##         Cl     1.6270                                      (IV-12)                                                                               ##STR272##         Cl     1.5442                                      (IV-13)                                                                               ##STR273##         Cl     140/0.5                                     (IV-14)                                                                               ##STR274##         Cl     122/0.1                                     (IV-15)                                                                               ##STR275##         Cl     110/0.1                                     (IV-16)                                                                               ##STR276##         Cl     120/0.2                                     (IV-17)                                                                               ##STR277##         Cl     140/0.2                                     (IV-18)                                                                               ##STR278##         Cl     140/0.2                                     (IV-19)                                                                               ##STR279##         Cl     160/0.2                                     (IV-20)                                                                               ##STR280##         Cl     120/0.3                                     (IV-21)                                                                               ##STR281##         Cl     138/0.1                                     (IV-22)                                                                              SC.sub.2 H.sub.5    Cl     1.4968                                      (IV-23)                                                                               ##STR282##         Cl     130/0.3                                     (IV-24)                                                                               ##STR283##         Cl     1,5843                                      (IV-25)                                                                               ##STR284##         Cl     160/0.3                                     (IV-26)                                                                               ##STR285##         Cl     158/0.3                                     (IV-27)                                                                               ##STR286##         Cl     155/0.3                                     (IV-28)                                                                               ##STR287##         Cl     1,5575                                      (IV-29)                                                                              S(CH.sub.2).sub.11CH.sub.3                                                                        Cl     1,4775                                      (IV-30)                                                                               ##STR288##         Cl     1,6065                                      (IV-31)                                                                               ##STR289##         Cl     1,5951                                      (IV-32)                                                                               ##STR290##         Cl     1,5514                                      (IV-33)                                                                               ##STR291##         Cl     1,5408                                      (IV-34)                                                                               ##STR292##         Cl     1,5748                                      (IV-35)                                                                               ##STR293##         Cl     1,5613                                      (IV-36)                                                                               ##STR294##         Cl     1,5738                                      (IV-37)                                                                               ##STR295##         Cl     1,5805                                      (IV-38)                                                                               ##STR296##         Cl     1,5858                                      (IV-39)                                                                               ##STR297##         Cl     1,5940                                      (IV-40)                                                                               ##STR298##         Cl     1,5840                                      (IV-41)                                                                               ##STR299##         Cl     1,5531                                      (IV-42)                                                                              SC(CH.sub.3).sub.3  Cl     1,4871                                      ______________________________________                                    

The following intermediates of the formula (V) ##STR300## in Table 3 areobtained according to the preparation examples recited above, usinganalogous reactants and reaction conditions, and the general statementsrelating to the processes:

                                      TABLE 3                                     __________________________________________________________________________    Example                                    Melting Point (°C.)         No.  R.sup.2            R.sup.3            or n.sub.D.sup.20                  __________________________________________________________________________    (V-2)                                                                               ##STR301##                                                                                       ##STR302##        1.6347                             (V-3)                                                                               ##STR303##                                                                                       ##STR304##         84                                (V-4)                                                                               ##STR305##                                                                                       ##STR306##        176                                (V-5)                                                                               ##STR307##                                                                                       ##STR308##        1.5612                             (V-6)                                                                               ##STR309##                                                                                       ##STR310##        100                                (V-7)                                                                               ##STR311##                                                                                       ##STR312##        1.5590                             (V-8)                                                                               ##STR313##                                                                                       ##STR314##         50                                (V-9)                                                                               ##STR315##                                                                                       ##STR316##         96                                __________________________________________________________________________

The preparation of the propene derivatives of the formulae (VIII) and(IX) which can be used as intermediates is illustrated by the followingexamples:

EXAMPLE α ##STR317##

A solution of 64.25 g (0.5 mol) of 4-chlorophenol in 100 ml of acetoneis added dropwise to a mixture of 125 g (1 mol) of3-chloro-2-chloromethyl-propene and 34.5 g (0.25 mol) of potassiumcarbonate in 500 ml of acetone at 60° C. The mixture is subsequentlystirred at room temperatures for 18 hours and filtered and the filtrateis concentrated. The oily residue is dissolved in methylene chloride andthe solution is washed once with 200 ml of 10% strength sodium hydroxidesolution and then twice with in each case 500 ml of water, dried oversodium sulphate and concentrated. The oily residue is distilled. 43.2 g(41.5% of theory) of 2-chloromethyl-3-(4-chlorophenoxy)-propene (ExampleVIII-1) of boiling point 80° to 90° C./0.05 mbar are obtained.

10.7 g of 3-(4-chlorophenoxy)-2-(4-chlorophenoxymethyl)-propene (ExampleIX-1) of melting point 72° C. are obtained from the distillation residueafter stirring with diisopropyl ether.

EXAMPLE β ##STR318##

A mixture of 25 g (0.2 mol) of 3-chloro-2-chloromethyl-propene, 27.6 g(0.4 mol) of 1,2,4-triazole and 27.6 g (0.2 mol) of potassium carbonatein 200 ml of acetone is heated under reflux for 15 hours. After cooling,the mixture is filtered and the filtrate is concentrated in vacuo. Theoily residue is chromatographed (silica gel 60, Merck, chloroform). 23 g(63% of theory) of3-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-yl-methyl)-propene of meltingpoint 52° C. are obtained.

USE EXAMPLES

The compounds shown below are used as comparison substances in theexample which follows:

    ______________________________________                                        (A)                                                                                 ##STR319##              known from DE-OS (German Published Specifica                                  tion) 2,820,489                                 (B)                                                                                 ##STR320##              known from DE-OS (German Published Specifica                                  tion) 3,018,865                                 (C)                                                                                 ##STR321##              known from DE-OS (German Published Specifica                                  tion) 3,018,865                                 (D)                                                                                 ##STR322##              known from DE-OS (German Published Specifica                                  tion) 3,018,865                                 (E)                                                                                 ##STR323##              known from EP-OS (European Published                                          Specification) 44,605                           ______________________________________                                    

EXAMPLE A Antimycotic in vivo activity (oral) in candidosis of mice

Description of the experiment:

Mice of the SPF-CF₁ type were infected intravenously with 1-2×10⁶logarithmically growing Candida cells, which are suspended inphysiological sodium chloride solution. The animals were treated orallywith in each case 50-100 mg/kg of body weight of the product one hourbefore and seven hours after the infection.

Results:

Untreated animals died 3 to 6 days after infection. The survival rate onthe 6th day after infection was about 5% in the case of the untreatedcontrol animals.

In this test, for example, compounds 1, 3, 4, 8, 11 and 12 according tothe invention exhibited a better action than compounds (A), (B), (C),(D) and (E) known from the prior art.

    ______________________________________                                        Explanation of symbols:                                                       ______________________________________                                        +++++    = very good action                                                                          =     90% survivors on the                                                          6th day after infection                          ++++     = good action =     80% survivors on the                                                          6th day after infection                          +++      = action      =     60% survivors on the                                                          6th day after infection                          ++       = slight action                                                                             =     40% survivors on the                                                          6th day after infection                          +        = trace of action                                                                           =     40% survivors on the                                                          6th day after infection                          n.a.     = no action                                                          ______________________________________                                    

                  TABLE A                                                         ______________________________________                                        Antimycotic in vivo activity (oral) in candidosis of mice                     ______________________________________                                        Active compound  Action                                                       (A) (known)      n.a.                                                         (B) (known)      n.a.                                                         (C) (known)      n.a.                                                         (D) (known)      n.a.                                                         (E) (known)      n.a.                                                         Compounds according to the preparation examples:                              1                   +++++                                                     3                   +++++                                                     4                   +++                                                       8                   +++++                                                     11                  +++++                                                     12                  +++++                                                     Example B/formulations                                                        1. Solution:                                                                  Active compound according to the formula (I)                                                             10 g                                               Alcohol, pure (96% strength)                                                                             300 g                                              Isopropyl myristate        526 g                                                                         836 g                                              2. Cream:                                                                     Active compound according to the formula (I)                                                             10 g                                               Arlacel 60                 20 g                                               (Sorbitan monostearate) Tween 60                                                                         15 g                                               Polyoxyethylene(2)-sorbitan monostearate                                      Spermaceti, synthetic      30 g                                               (Mixture of esters of saturated C.sub.14 -C.sub.18                            fatty acids and C.sub.14 -C.sub.18 fatty alcohols)                            Lanette O                  100 g                                              (Mixture of cetyl alcohol and stearyl alcohol)                                Entanol G                  135 g                                              (2-Octyl-dodecanol)                                                           Benzyl alcohol             10 g                                               Water, demineralised       680 g                                                                         1,000 g                                            ______________________________________                                    

We claim:
 1. A substituted tert.-butanol derivative of the formula##STR324## in which R¹ and R² are identical or different and representimidazol-1-yl, 1,2,4-triazol-1-yl; 1,2,4-triazol-4-yl or pyrazol-1-ylandR³ represents phenoxy, phenylthio, phenylimino orphenyl-N-alkyl-amino with 1 to 4 carbon atoms in the alkyl part, eachradical being optionally monosubstituted or polysubstituted by identicalor different substituents, said substituents or phenyl in each casebeing: halogen, alkyl with 1 to 5 carbon atoms, alkoxy and alkylthiowith in each case 1 to 4 carbon atoms; halogenoalkyl, halogenoalkoxy andhalogenoalkylthio with in each case 1 to 4 carbon atoms and 1 to 5identical or different halogen atoms; cycloalkyl with 5 or 6 carbonatoms; nitro, cyano, hydroxycarbonyl, alkylcarbonyl or alkoxycarbonylwith in each case 1 to 4 carbon atoms in the alkyl part, phenyl orphenoxy which is optionally monosubstituted or polysubstituted byidentical or different substituents selected from the group consistingof halogen, nitro, trifluoromethyl and alkyl, with 1 to 2 carbon atoms,the aldehyde group or the oxime or hydroxyiminoethyl ormethoxyiminomethyl radical.
 2. A substituted tert.-butanol derivative ofclaim 1, of the formula (I) ##STR325## in which R¹ and R² are identicalor different and represent imidzol-1-yl; 1,2,4-triazol-1-yl;1,2,4-triazol-4-yl or pyrazol-1-yl, andR³ represents phenoxy,phenylthio, phenylamino or phenyl-N-alkyl-amino with 1 or 2 carbon atomsin the alkyl part, each radical optionally being monosubstituted or di-or tri-substituted by identical or different substituents, saidsubstituents on the phenyl in each case being: fluorine, chlorine,bromine, methyl, ethyl, isopropyl, tert.-butyl, 2-methyl-but-2-yl,methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, cyclohexyl, nitro, cyano, hydroxycarbonyl,methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, or phenyl or phenoxy,in each case optionally monosubstituted or di- or tri-substituted byidentical or different substituents selected from the group consistingof chlorine, nitro, trifluoromethyl and methyl, or the aldehyde group,hydroxyiminoethyl or methoxyiminomethyl.
 3. A compound of claim 1 whichis2-(4-Chlorophenoxymethyl)-1,3-di-(1,2,4-triazol-1-yl)-2-hydroxypropane.4. A compound of claim 1 which is2-(2,4-Dichlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxypropane.5. A compound of claim 1 which is2-(2,4-Dichlorophenoxymethyl)-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-4-yl)-propane.6. A compound of claim 1 which is2-(4-Chlorophenylthiomethyl)-1,3-di-(1,2,4-triazol-1-yl)-2-hydroxypropane.7. A compound of claim 1 which is1,3-Di-(1,2,4-triazol-1-yl)-2-(4-fluoro-phenoxymethyl)-2-hydroxypropane.8. A compound of claim 1 which is1,3-Di-(1,2,4-triazol-1-yl)-2-(4-phenylphenoxymethyl)-2-hydroxypropane.9. A pharmaceutical composition containing as an active ingredient anantimycotically effective amount of a compound of claim 1 in admixturewith an inert pharmaceutical carrier.
 10. A pharmaceutical compositionof claim 9 in the form of a sterile or physiologically isotonic aqueoussolution.
 11. A composition according to claim 9 containing from 0.5 to90% by weight of the said active ingredient.
 12. A medicament in dosageunit form comprising an antimycotically effective amount of a compoundof claim 1 and an inert pharmaceutical carrier.
 13. A medicament ofclaim 12 in the form of tablets, pills, dragees, capsules, ampoules orsuppositories.
 14. A method of combatting mycosis in warm-bloodedanimals which comprises administering to said animals an antimycoticallyeffective amount of an active compound according to claim 1 eitheralone, or in admixture with a diluent or in the form of a medicament.15. A method according to claim 14 in which the active material isadministered in an amount of about 50 to about 300 mg/kg body weight perday.
 16. A method according to claim 14 in which the active compound isadministered orally or parenterally.